Abstract There are numerous examples of a vaccine that results in neutralizing antibodies in one population, but not others. Rotavirus, polio, cholera, and tuberculosis (TB) are examples. BCG vaccination for TB has significantly higher rates of protection the further north the vaccine is used. Reasons for differences in vaccine efficacy are unknown with genetic or environmental factors thought to be important factors. An interesting parallel observation is that population based measures of CD4 T cells also vary geographically, with people living in northern latitudes having significantly greater numbers of CD4 T cells than people living close to the equator. In our studies of mechanisms of loss of CD4 T cells in HIV infection, we showed that HIV replication in lymphoid tissues caused inflammatory damage to the Fibroblastic Reticular Cell network (FRCn) in the form of collagen deposition into the network. The FRCn is the primary source of IL-7 outside of the thymus and loss of the network results in decreased production of IL-7 and the net result is increased T cell apoptosis. Our data suggest this is a significant mechanism of CD4 loss in HIV infection. We speculated that infections other than HIV might cause inflammatory damage to the FRCn and might be a reason CD4 T cells are depleted in populations of people living in tropical climates, especially developing economies. This may be a factor in limiting vaccine responses in these populations. We studied lymph nodes in HIV negative people living in Uganda and show in our preliminary data that the FRCn and CD4 T cell populations are depleted and that levels of inflammatory cytokines and tissue markers of immune activation are elevated. We vaccinated them with yellow fever vaccine (YFV) and found the peak neutralizing antibody titer correlated to our quantitative analyses of the FRCn and measures of inflammatory cytokines and immune activation. These data support our model of inflammatory damage to the architecture of lymph nodes as a contributing factor to failure of vaccine efficacy in the developing world. We now propose to build on these preliminary studies by giving YFV to a larger cohort of Ugandans but also to add a cohort in Minnesota where we have shown limited inflammatory damage to the FRCn. We will conduct extensive immunologic and microbial investigations of factors that limit durable immune responses. Our hypothesis is that endemic infections other than HIV can cause LN inflammation and collagen damage to the FRCn which will lead to CD4 T cell depletion and impaired vaccine responses.